TRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells
TRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells
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TRIM66 读取未修饰的 H3R2K4 和 H3K56ac 以响应胚胎干细胞中的 DNA 损伤
DOI：
10.1038/s41467-019-12126-4
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发表时间：
2019-09-19
影响因子：
16.6
通讯作者：
Shi, Yunyu
中科院分区：
文献类型：
--
作者：
Chen, Jiajing;Wang, Zikang;Shi, Yunyu
通过“阅读器”蛋白内的不同结构域识别特定的染色质修饰在维持基因组稳定性中起关键作用。然而，这一过程所涉及的具体机制仍不清楚。在这里，我们报告的PHD-Bromo串联结构域的三重基序包含66（TRIM 66）识别未修饰的H3 R2-H3 K4和乙酰化H3 K56。Trim 66的异常缺失导致胚胎干细胞（ESC）中严重的DNA损伤和基因组不稳定性。此外，我们发现TRIM 66对组蛋白修饰的识别对于ESCs中的DNA损伤修复（DDR）至关重要。TRIM 66招募Sirt 6使H3 K56 ac脱乙酰化，负调节H3 K56 ac的水平并促进DDR的启动。重要的是，Trim 66缺陷型囊胚也表现出更高水平的H3 K56 ac和DNA损伤。总的来说，目前的研究结果表明TRIM 66在胚胎干细胞的DDR中起着至关重要的作用，建立了组蛋白阅读器和维持基因组稳定性之间的关系。
Recognition of specific chromatin modifications by distinct structural domains within "reader" proteins plays a critical role in the maintenance of genomic stability. However, the specific mechanisms involved in this process remain unclear. Here we report that the PHD-Bromo tandem domain of tripartite motif-containing 66 (TRIM66) recognizes the unmodified H3R2-H3K4 and acetylated H3K56. The aberrant deletion of Trim66 results in severe DNA damage and genomic instability in embryonic stem cells (ESCs). Moreover, we find that the recognition of histone modification by TRIM66 is critical for DNA damage repair (DDR) in ESCs. TRIM66 recruits Sirt6 to deacetylate H3K56ac, negatively regulating the level of H3K56ac and facilitating the initiation of DDR. Importantly, Trim66-deficient blastocysts also exhibit higher levels of H3K56ac and DNA damage. Collectively, the present findings indicate the vital role of TRIM66 in DDR in ESCs, establishing the relationship between histone readers and maintenance of genomic stability.